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The Role of Decreased Levels of Neuronal Autophagy in Increased Susceptibility to Post-traumatic Epilepsy

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Abstract

Post-traumatic epilepsy (PTE) caused by mild TBI (mild traumatic brain injury, mTBI) has a high incidence and poor prognosis, but its mechanisms are unclear. Herein, we investigated the role of reduced levels of neuronal autophagy during the latency period in the increased susceptibility to PTE. In the study, a gentle whole-body mechanical trauma rat model was prepared using Noble-Collip drums, and the extent of injury was observed by cranial CT and HE staining of hippocampal tissue. The incidence of epilepsy and its seizure form were observed 7–90 days after mTBI, and electroencephalography (EEG) was recorded during seizures in rats. Subcortical injection of non-epileptogenic dose of ferrous chloride (FeCl2) was used to observe the changes of PTE incidence after mTBI. Western blot and Real-time PCR were used to detect the level of autophagy in hippocampal cells at different time points during the latency period of PTE, and its incidence was observed after up-regulation of autophagy after administration of autophagy agonist—rapamycin. The results showed that mTBI was prepared by Noble-Collip drum, which could better simulate the clinical mTBI process. There was no intracerebral hemorrhage and necrosis in rats, no early-onset seizures, and the incidence of PTE after mTBI was 26.7%. The incidence of PTE was 56.7% in rats injected cortically with FeCl2 at a dose lower than the epileptogenic dose 48 h after mTBI, and the difference was significant compared with no FeCl2 injection, suggesting an increased susceptibility to PTE after mTBI. Further study of neuronal autophagy during PTE latency revealed that autophagy levels were reduced, and the incidence of PTE was significantly reduced after administration of rapamycin to upregulate autophagy. Taken together, the decreased level of neuronal autophagy during the latency period may be a possible mechanism for the increased susceptibility to PTE after mTBI.

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Data Availability

All data generated or analyzed during this study are included in this published article and will be made available on reasonable request.

References

  1. Scheffer IE, Berkovic S, Capovilla G et al (2017) ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–521. https://doi.org/10.1111/epi.13709

    Article  PubMed  PubMed Central  Google Scholar 

  2. Maas AIR, Menon DK, Adelson PD et al (2017) Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol 16:987–1048. https://doi.org/10.1016/S1474-4422(17)30371-x

    Article  PubMed  Google Scholar 

  3. Dixon C, Lyeth B, Povlishock J et al (1987) A fluid percussion model of experimental brain injury in the rat. J Neurosurg 67:110–119. https://doi.org/10.3171/jns.1987.67.1.0110

    Article  CAS  PubMed  Google Scholar 

  4. Marmarou A, Foda M, van den Brink W et al (1994) A new model of diffuse brain injury in rats. Part I: pathophysiology and biomechanics. J Neurosurg 80:291–300. https://doi.org/10.3171/jns.1994.80.2.0291

    Article  CAS  PubMed  Google Scholar 

  5. Dixon CE, Clifton GL, Lighthall JW et al (1991) A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253–262. https://doi.org/10.1016/0165-0270(91)90104-8

    Article  CAS  PubMed  Google Scholar 

  6. Efendioglu M, Basaran R, Akca M et al (2020) Combination therapy of gabapentin and N-acetylcysteine against posttraumatic epilepsy in rats. Neurochem Res 45:1802–1812. https://doi.org/10.1007/s11064-020-03042-x

    Article  CAS  PubMed  Google Scholar 

  7. Wang J, Lu K, Liang F et al (2013) Decreased autophagy contributes to myocardial dysfunction in rats subjected to nonlethal mechanical trauma. PLoS ONE 8:e71400. https://doi.org/10.1371/journal.pone.0071400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tao L, Liu HR, Gao F et al (2005) Mechanical traumatic injury without circulatory shock causes cardiomyocyte apoptosis: role of reactive nitrogen and reactive oxygen species. Am J Physiol Heart Circ Physiol 288:H2811-2818. https://doi.org/10.1152/ajpheart.01252.2004

    Article  CAS  PubMed  Google Scholar 

  9. Hunt RF, Boychuk JA, Smith BN (2013) Neural circuit mechanisms of post-traumatic epilepsy. Front Cell Neurosci 7:89. https://doi.org/10.3389/fncel.2013.00089

    Article  PubMed  PubMed Central  Google Scholar 

  10. Barranco C (2015) Activate autophagy to prevent cartilage degeneration? Nat Rev Rheumatol 11:127. https://doi.org/10.1038/nrrheum.2015.12

    Article  PubMed  Google Scholar 

  11. Chen Y, Klionsky DJ (2011) The regulation of autophagy—unanswered questions. J Cell Sci 124(Pt 2):161–170. https://doi.org/10.1242/jcs.064576

    Article  CAS  PubMed  Google Scholar 

  12. Carloni S, Buonocore G, Balduini W (2008) Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 32(3):329–339. https://doi.org/10.1016/j.nbd.2008.07.022

    Article  PubMed  Google Scholar 

  13. Jiang P, Mizushima N (2014) Autophagy and human diseases. Cell Res 24(1):69–79. https://doi.org/10.1038/cr.2013.161

    Article  CAS  PubMed  Google Scholar 

  14. Wang D, Tian M, Qi Y et al (2015) Jinlida granule inhibits palmitic acid induced-intracellular lipid accumulation and enhances autophagy in NIT-1 pancreatic β cells through AMPK activation. J Ethnopharmacol 161:99–107. https://doi.org/10.1016/j.jep.2014.12.005

    Article  CAS  PubMed  Google Scholar 

  15. Kim JH, Hong SK, Wu PK et al (2014) Raf/MEK/ERK can regulate cellular levels of LC3B and SQSTM1/p62 at expression levels. Exp Cell Res 327(2):340–352. https://doi.org/10.1016/j.yexcr.2014.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sahani MH, Itakura E, Mizushima N (2014) Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending ontranscriptional upregulation and autophagy-derived amino acids. Autophagy 10(3):431–441. https://doi.org/10.4161/auto.27344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Clark RS, Bayir H, Chu CT et al (2008) Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness. Autophagy 4:88–90. https://doi.org/10.4161/auto.5173

    Article  CAS  PubMed  Google Scholar 

  18. Wong M (2013) Cleaning up epilepsy and neurodegeneration: the role of autophagy in epileptogenesis. Epilepsy curr 13:177–178. https://doi.org/10.5698/1535-7597-13.4.177

    Article  PubMed  PubMed Central  Google Scholar 

  19. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32(3):281–294. https://doi.org/10.1016/0013-4694(72)90177-0

    Article  CAS  PubMed  Google Scholar 

  20. Ferguson PL, Smith GM, Wannamaker BB et al (2010) A population-based study of risk of epilepsy after hospitalization for traumatic brain injury. Epilepsia 51:891–898. https://doi.org/10.1111/j.1528-1167.2009.02384.x

    Article  PubMed  Google Scholar 

  21. Gómez PA, de-la-Cruz J, Lora D et al (2014) Validation of a prognostic score for early mortality in severe head injury cases. J Neurosurg 121:1314–1322. https://doi.org/10.3171/2014.7.JNS131874

    Article  PubMed  Google Scholar 

  22. Register-Mihalik JK, Sarmiento K, Vander Vegt CB et al (2019) Considerations for athletic trainers: a review of guidance on mild traumatic brain injury among children from the centers for disease control and prevention and the national athletic trainers’ association. J Athl Train 54:12–20. https://doi.org/10.4085/1062-6050-451-18

    Article  PubMed  PubMed Central  Google Scholar 

  23. Eakin K, Miller JP (2012) Mild traumatic brain injury is associated with impaired hippocampal spatiotemporal representation in the absence of histological changes. J Neurotrauma 29:1180–1187. https://doi.org/10.1089/neu.2011.2192

    Article  PubMed  Google Scholar 

  24. Jeter CB, Hergenroeder GW, Hylin MJ et al (2013) Biomarkers for the diagnosis and prognosis of mild traumatic brain injury/concussion. J Neurotrauma 30:657–670. https://doi.org/10.1089/neu.2012.2439

    Article  PubMed  Google Scholar 

  25. Jordan BD (2013) The clinical spectrum of sport-related traumatic brain injury. Nat Rev Neurol 9:222–230. https://doi.org/10.1038/nrneurol.2013.33

    Article  CAS  PubMed  Google Scholar 

  26. Piccenna L, Shears G, O’Brien TJ (2017) Management of post-traumatic epilepsy: an evidence review over the last 5 years and future directions. Epilepsia Open 2:123–144. https://doi.org/10.1002/epi4.12049

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen Z, Venkat P, Seyfried D et al (2017) Brain-heart interaction: cardiac complications after stroke. Circ Res 121:451–468. https://doi.org/10.1161/CIRCRESAHA.117.311170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Roux A, Muller L, Jackson SN et al (2016) Mass spectrometry imaging of rat brain lipid profile changes over time following traumatic brain injury. J Neurosci Methods 272:19–32. https://doi.org/10.1016/j.jneumeth.2016.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Raymont V, Salazar AM, Lipsky R et al (2010) Correlates of posttraumatic epilepsy 35 years following combat brain injury. Neurology 75:224–229. https://doi.org/10.1212/WNL.0b013e3181e8e6d0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gao Y, Luo CL, Li LL et al (2017) IL-33 provides neuroprotection through suppressing apoptotic, autophagic and NF-kappaB-mediated iinflammatory pathways in a rat model of recurrent neonatal seizure. Front Mol Neurosci 10:423. https://doi.org/10.3389/fnmol.2017.00423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li Q, Han Y, Du J et al (2018) Recombinant human erythropoietin protects against brain injury through blunting the mTORC1 pathway in the developing brains of rats with seizures. Life Sci 194:15–25. https://doi.org/10.1016/j.lfs.2017.12.014

    Article  CAS  PubMed  Google Scholar 

  32. Yuen AW, Sander JW (2014) Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy. Epilepsy Behav 33:110–114. https://doi.org/10.1016/j.yebeh.2014.02.026

    Article  PubMed  Google Scholar 

  33. Anovadiya AP, Sanmukhani JJ, Tripathi CB (2012) Epilepsy: novel therapeutic targets. J Pharmacol Pharmacother 3:112–117. https://doi.org/10.4103/0976-500X.95505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

National Natural Science Foundation of China (No. 81501132).

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Authors and Affiliations

  1. Department of Neurology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province, China

    Jie Wang, Fang Zhang, Yuchen Li & Huijun Shen

  2. Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China

    Xiaoyang Chai

  3. Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, Shanxi Province, China

    Keyi Lu

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  1. Jie Wang
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  2. Xiaoyang Chai
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  3. Fang Zhang
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  4. Yuchen Li
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  5. Huijun Shen
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  6. Keyi Lu
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Contributions

JW: topic selection, animal experiments, thesis writing; XC: animal experiments, thesis writing; FZ: data collection and processing; YL: data processing and analysis; HS: data collection and processing; KL: thesis revision, experimental guidance.

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Correspondence to Jie Wang or Keyi Lu.

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The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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Ethic certification was approved by ethics Committee of Shanxi Medical University.

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Wang, J., Chai, X., Zhang, F. et al. The Role of Decreased Levels of Neuronal Autophagy in Increased Susceptibility to Post-traumatic Epilepsy. Neurochem Res 48, 909–919 (2023). https://doi.org/10.1007/s11064-022-03814-7

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